ZA200302633B - 2-Guianidino-4-arylquinazolines. - Google Patents

2-Guianidino-4-arylquinazolines. Download PDF

Info

Publication number
ZA200302633B
ZA200302633B ZA200302633A ZA200302633A ZA200302633B ZA 200302633 B ZA200302633 B ZA 200302633B ZA 200302633 A ZA200302633 A ZA 200302633A ZA 200302633 A ZA200302633 A ZA 200302633A ZA 200302633 B ZA200302633 B ZA 200302633B
Authority
ZA
South Africa
Prior art keywords
hci
chs
formula
compounds
solvates
Prior art date
Application number
ZA200302633A
Inventor
Rolf Gericke
Claudia Wilm
Norbert Beier
Original Assignee
Merck Patent Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Publication of ZA200302633B publication Critical patent/ZA200302633B/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/84—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Oncology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Communicable Diseases (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Description

® ov 2-Guanidino-4-arylquinazolines
The invention relates to compounds of the formula
Ar
R2 ~ °N x
Ny
R1 in which 5.6 6
NR'R NR
Y IS or
NZ NN
RS
1 5 1
Ar is phenyl or naphthyl, each of which is unsubstituted or monosubstituted by R® and/or R*,
RR?
R® and R* are each, independently of one another, H, A, OA, Hal, CFs, OH,
NO,, NH,, NHA, NA;, NH-CO-A, NH-CO-Ph, SA, SO-A, SOx-A,
SO.-Ph, CN, OCF3, CO-A, CO,H, COA, CO-NH2, CO-NHA,
CO-NA;, SO.NH,, SO,NHA, SO2NA,, or phenyl which is unsubstituted or monosubstituted or polysubstituted by A, OA,
Hal or CF,
A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,
Hal is F, Cl, Brorl
R® R®
R’ and R® are each, independently of one another, H, A, or phenyl which is unsubstituted or monosubstituted or polysubstituted by A, OA,
Hal or CFs, where R® and R”, R® and R® and R’ and R® are able to form 5-7-membered rings,
J
® = and their salts and solvates, with the proviso that compounds in which R®
R® R’ and R® are simultaneously H and none of the radicals R', R? R® and
R*is OH, NO,, NH2, NHA, NA, NH-CO-A, NH-CO-Ph, SA, SO-A, SO2-A,
SO,-Ph, CN, OCF3, CO-A, COzH, COzA, CO-NHz, CO-NHA, CO-NA,,
SO,NH,, SO.NHA, SO2NA,, or phenyl which is unsubstituted or monosubstituted or polysubstituted by A, OA, Hal or CF3, are excluded.
The invention likewise relates to the use of the compounds of the formula and their salts and solvates as NHE-3 inhibitors.
Other inhibitors of the sodium/proton exchanger subtype 3 have already been described, for example in EP 0 825 178.
The compounds excepted by the proviso have already been described in
US 3,131,187, as has their use for other purposes.
Quinazolinylguanidine derivatives have been described by V.I. Shvedov et al. in Pharm. Chem. J. (Engl. transl.) 1980, 14, 532-538 or in Khim. Farm.
Zh. 1980, 14, 38-43, and by S.C.Bell et al. in J. Med. Pharm. Chem. 1962, 5, 63-69.
The invention had the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.
Surprisingly, it has been found that the compounds of the formula | and their salts are well tolerated and inhibit sodium/proton exchanger subtype 3.
The compounds of the formula | can be employed as medicament active ingredients in human and veterinary medicine.
It is known that the Na'/H" exchanger represents a family having at least six different isoforms (NHE-1 to NHE-6), all of which have already been cloned. While subtype NHE-1 is distributed ubiquitously in all tissues throughout the body, the other NHE subtypes are expressed selectively in specific organs, such as in the kidney or in the lumen wall and contra- luminal wall of the small intestine. This distribution reflects the specific
® vr functions that the various isoforms serve, namely on the one hand regulation of the intracellular pH and cell volume by subtype NHE-1 and on the other hand Na * absorption and resorption in the intestine and kidney by isoforms NHE-2 and NHE-3. Isoform NHE-4 has been found principally in the stomach. Expression of NHE-5 is restricted to the brain and neuronal tissue. NHE-S is the isoform that forms the sodium/proton exchanger in the mitochondria.
The isoform NHE-3 is expressed in particular in the apical membrane of the proximal renal tubuli; an NHE-3 inhibitor therefore exerts, inter alia, a protective action on the kidneys.
The therapeutic use of a selective inhibitor for NHE-3 isoforms is manifold.
NHE-3 inhibitors inhibit or reduce tissue damage and cell necrosis after pathophysiological hypoxic and ischaemic events which result in activation of the NHE activity, as is the case during renal ischaemia or during the removal, transport and reperfusion of a kidney during a kidney transplant.
The compounds of the formula | have a cytoprotective action in that they prevent the excessive absorption of sodium and water into the cells of organs undersupplied with oxygen.
The compounds of the formula | have a hypotensive action and are suitable as medicament active ingredients for the treatment of hypertonia.
They are furthermore suitable as diuretics.
The compounds of the formula |, alone or in combination with NHE inhibitors of other subtype specificity, have an antiischaemic action and can be used in the case of thromboses, atherosclerosis, vascular spasms, for the protection of organs, for example kidney and liver, before and during operations, and in the case of chronic or acute renal failure.
They can furthermore be used for the treatment of strokes, cerebral oedema, ischaemia of the nervous system, various forms of shock, for example allergic, cardiological, hypovolemic or bacterial shock, and for improving breathing drive in, for example, the following states: central sleep apnoea, cot death, postoperative hypoxia and other breathing disorders.
®
Through combination with a carboanhydrase inhibitor, breathing activity can be further improved.
The compounds of the formula | have an inhibiting effect on the prolifera- tion of cells, for example fibroblast cell proliferation and the proliferation of
S the smooth muscle cells, and can therefore be used for the treatment of illnesses in which cell proliferation is a primary or secondary cause.
The compounds of the formula | can be used against delayed complica- tions of diabetes, cancer illnesses, fibrotic ilinesses, endothelial dys- function, organ hypertrophia and hyperplasia, in particular in prostate hyperplasia or prostate hypertrophia.
They are furthermore suitable as diagnostic agents for the determination and differentiation of certain forms of hypertonia, atherosclerosis, diabetes and proliferative illnesses.
Since the compounds of the formula | also have an advantageous effect on the level of serum lipoproteins, they can be employed, alone or in combination with other medicaments, for the treatment of an increased blood fat level.
The invention relates to the use of compounds of the formula | according to
Claim 1 and their physiologically acceptable salts and/or solvates for the preparation of a medicament for the treatment of thrombosis, ischaemic states of the heart, of the peripheral and central nervous system and of strokes, ischaemic states of peripheral organs and extremities and for the treatment of shock states.
The invention furthermore relates to the use of compounds of the formula according to Claim 1 and their physiologically acceptable salts and/or solvates for the preparation of a medicament for use in surgical operations and organ transplants and for the preservation and storage of transplants for surgical measures.
The invention also relates to the use of compounds of the formula according to Claim 1 and their physiologically acceptable salts and/or solvates for the preparation of a medicament for the treatment of illnesses in which cell proliferation is a primary or secondary cause, for the treatment or prophylaxis of disorders of fat metabolism or disturbed breathing drive.
®
The invention furthermore relates to the use of compounds of the formula according to Claim 1 and their physiologically acceptable salts and/or solvates for the preparation of a medicament for the treatment of renal ischaemia, ischaemic intestinal ilinesses or for the prophylaxis of acute or chronic renal ilinesses.
Methods for the identification of substances which inhibit sodium/proton exchanger subtype 3 are described, for example, in US 5,871,919.
The compounds of the formula | are, in addition, suitable for the treatment of bacterial and parasitic illnesses.
For all radicals in the compounds of the formula | which occur more than once, such as, for example, A, their meanings are independent of one another.
The term hydrates is taken to mean, for example, the hemi-, mono- or dihydrates, and the term solvates is taken to mean, for example, alcohol addition compounds, such as, for example, with methanol or ethanol.
In the formulae above, A is alkyl, is linear or branched, and has 1, 2, 3, 4, 5 or 6 carbon atoms. A is preferably methyl, furthermore ethyl, propyl, iso- propyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethyipropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-,1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, or 1,1,2- or 1,2,2-trimethylpropyl.
OA is preferably methoxy, ethoxy, propoxy, isopropoxy or butoxy.
Hal is preferably F, Cl or Br, but also |, in particular F, Cl or Br.
Above and below, Ph is an unsubstituted phenyl radical unless stated otherwise.
® vr
Ar is preferably unsubstituted phenyl or naphthyl, furthermore preferably phenyl or naphthyl which is monosubstituted, for example, by A, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, propoxy, butoxy or CFs.
Ar is particularly preferably phenyl which is unsubstituted or mono- substituted by A, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, propoxy, butoxy or CFs.
R® R® R” and R® are preferably simultaneously H or, independently of one another, H or A, which is as defined above. if R®> and R’ together form a ring, Y preferably adopts one of the following structures:
AVN NR® hn or ~ A “Pn Lr \
R® n in which R® and R® are as defined above, and nis 1, 2 or 3, preferably 1 or 2.
If R” and R® together form a ring, Y preferably adopts one of the following structures: , a or 5 ~ ps or ~~
N” °N 2 \, N 2
R in which R® and R® are as defined above, and nis 1, 2 or 3, preferably 1 or 2
If R® and R® together form a ring, Y preferably adopts one of the following structures:
®
CY NR'R®
N or “nA
PRR a! in which R” and R® are as defined above, and nis 1, 2 or 3, preferably 1 or 2.
Accordingly, the invention relates in particular to the use of the compounds of the formula | in which at least one of the said radicals has one of the preferred meanings indicated above, and to the use thereof. Some pre- ferred groups of compounds may be expressed by the following sub- formulae la to le, which conform to the formula | and in which the radicals not designated in greater detail have the meaning indicated in the formula 1, but in which inla R' is H, OH, OA, SA or Hal, in particular H, OH, OCH; or
CHs; 0 inlb R' is H, OH, OA, SA or Hal, in particular H, OH, OCH; or
CHs,
R? is H, Hal, OH, A, NH, NO; or CN, in particular H, CI,
OH, CHs or NH; nlc R is H, OH, OA, SA or Hal, in particular H, OH, OCH; or
CH,
R? is H, Hal, OH, A, NH,, NO; or CN, in particular H, Cl,
OH, CH3 or NH,
Ar is phenyl ; nid R' is H, OH, OA, SA or Hal, in particular H, OH, OCH; or
CH; - R? is H, Hal, OH, A, NH, NO, or CN, in particular H, Cl,
OH, CHs3 or NH,
Ar is phenyl,
° ”
R® is H, A, NH; or SA, in particular H or CHj; inle R is H, OH, OA, SA or Hal, in particular H, OH, OCHs or
CHa,
R? is H, Hal, OH, A. NH,, NO, or CN, in particular H, Cl,
OH, CHs; or NH,
Ar is phenyl,
R3 is H, A, NH, or SA, in particular H or CH,
R* is H, Hal, NH, or NO3, in particular H or NH.
Preference is further given to compounds of the formula | and their salts and solvates in which R is simultaneously H, Ar is phenyl and at least one of the radicals R', R?, R%*and R* have one of the following meanings:
OH, NO,, NH, NHA, NA;, NH-CO-A, NH-CO-Ph, SA, SO-A, SO2-A,
S0,-Ph, CN, OCF3, CO-A, CO2H, COA, CO-NH2, CO-NHA, CO-NA;,
SO-NH,, SO.NHA, SO2NA,, or phenyl which is unsubstituted or mono- substituted or polysubstituted by A, OA, Hal or CFs. Of these compounds, particular preference is given to those whose radical R'is CI, in particular in position 6, and those compounds whose radical R? is methyl, in particular in position 4’.
Preference is also given to compounds of the formula | and their salts and solvates in which the radicals R®, R®, R” and R® are simultaneously H. Of these compounds, particular preference is given to those whose radical R' is Cl, in particular in position 6, and compounds whose radical R3is methyl, in particular in position 4’, and compounds whose radical R*is NH, in particular in position 2’.
Compounds of the formula | whose radical R® is methyl, in particular in position 4’, have a particularly pronounced selectivity of the binding to the
NHE-3 receptor.
Compounds of the formula | whose radical R* is NH,, in particular in position 2’, exhibit particularly good solubility in aqueous solutions.
® vr
Compounds of the formula | in which R' is H, R? is Cl in position 6 and R® is methyl in position 4" are preferred. Very particular preference is given to compounds of the formula | whose radical R* is additionally NH; in position 2.
Particular preference is given to the compounds of the formulae If to Ik: r® 0 ; rR? 2
Ree
Se
R' rR?
CL
R' Sy
Rr
C : rR? 2
R' oy ~%
Rr?
C
2 > O
Sey
R'
® hs
Rr® rR 94:
NS
R' oy r® rR?
C : 2
IN 6
R' Sy in which R' RZ R® R*and Y are as defined above, and R’ is preferably H,
OH, OA, SA or F, in particular H, OH, OCH; or CHa. R' in the formulae If to
Ik is very particularly preferably H.
R? is preferably H, Cl, A, NH, NO, SCHa3, SOCHj3, SO,CH3, OCHs3, OH,
CN, CF3, OCF3 or F, in particular H, Cl, F, Br, OH, CHs, NO, or NH. R%in the formulae If to Ik is very particularly preferably Cl.
R> is preferably H, Cl, A, NH,, NO,, SCHs, CN, CoHs, OCF; or CeHs, in particular H, A or CHa. R? in the formula If to Ik is very particularly preferably CHs.
R* is preferably H, F, NH, or NO, in particular H or NH,. R* in the formulae
If to Ik is very particularly preferably NH.
Y in the formulae If to Ik is as defined above. Y therein preferably adopts one of the following meanings: 7
NE or oN NH,
H
° A
NH, NH 7 ~N J a or N NHCH,
H
Z or ~
SN” NHC H, N™ “NHC,Hs
H
NH, NH 7 or ~ J
Pe, N™ “NHC,Hs
H
NH, NH ~ fo) ~ J “er, ' N™ NCH),
H
Y particularly preferably has one of the following meanings:
NH, NH ~ ~ J
NEA
H
NH, NH py wn or “Por,
H .
Particular preference is furthermore given to the following compounds 11 to 110 and their salts and solvates:
N-(6-chioro-4-phenylquinazolin-2-y!)-N'-methylguanidine 11
N-(6-chioro-4-p-tolyiquinazolin-2-yl)-N'-methylguanidine 12
N-[6-chloro-4-(2-nitrophenyl)quinazolin-2-yl}-N'-methyl- I3 guanidine
N-[4-(2-aminophenyl)-6-chloroquinazolin-2-yl}-N'-methyl- 14 guanidine
Py -12 -
N-[6-chloro-4-(4-methyl-2-nitrophenyl)quinazolin-2-yl}-N'- 15 methylguanidine
N-[4-(2-amino-4-methylphenyl)-6-chloroquinazolin-2-yl}-N'- 16 methylguanidine
S N-[6-chloro-4-(2-nitrophenyl)quinazolin-2-yllguanidine I7
N-[4-(2-aminophenyl)-6-chloroquinazolin-2-yllguanidine I8
N-[6-chioro-4-(4-methyl-2-nitrophenyl)quinazolin-2-yl}- 19 guanidine
N-[4-(2-amino-4-methylphenyl)-6-chloroquinazolin-2-yl}- 10 guanidine
The hydrochlorides and p-toluenesulfonates of the compounds of the formulae 11 to 110 are very particularly preferred.
The compounds of the formula | and also the starting materials for their preparation are, in addition, prepared by methods known per se, as described in the literature (for example in the standard works, such as
Houben-Weyl, Methoden der organischen Chemie [Methods of Organic
Chemistry], Georg-Thieme-Verlag, Stuttgart), to be precise under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants which are known per se, but are not mentioned here in greater detail.
The starting materials can, if desired, also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately converted further into the compounds of the formula I.
The 2guanidineo-4-arylquinazolines of the formula | are preferably prepared by reacting o-aminophenyl ketones o-aminonaphthyl ketones of the formula Il
Ar
R2 oc
I
Ri NH,
® -13- in which R', RZ and Ar are as defined in Claim 1, with 1-cyanoguanidine or a correspondingly N-alkylated or N-arylated 1-cycanoguanidine of the formula NC-Y, in which Y is as defined above.
The reaction can be carried out in an inert solvent.
Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethy! ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the said solvents.
DMF, water or an alcohol is preferably used.
The reaction is very particularly preferably carried out without a solvent, i.e. in the melt, at temperatures between 100 and 200°C.
Of advantage is the presence of an acidic catalyst, such as AICl3, TiCls, p-toluenesulfonic acid, BF, acetic acid, sulfuric acid, oxalic acid, POCI; or phosphorus pentoxide.
A preferred variant comprises employing one of the reactants already as a salt, for example as the hydrochloride.
° oH
A further valuable method for the preparation of the compounds of the formula | comprises reacting, instead of a compound of the formula NC-Y, a compound of the formula Iii
S HN=CX-Y IH in which
X is —S-alkyl, -S-aryl, O-alkyl or O-aryl, and alkyl is preferably as defined above for A, and aryl is preferably as defined above for Ar, with a compound of the formula Il.
Finally, the compounds of the formula | can be prepared by reaction of 2-chloro-4-arylquinazolines of the formula IV
Ar
R2
Zn
Iv
Se
R? in which Ar, R' and R? are as defined above, with a compound of the formula HY, in which Y is as defined above. HY is particularly preferably guanidine.
A base of the formula | can be converted into the associated acid-addition salt using an acid, for example by reaction of equivalent amounts of the base and the acid in an inert solvent, such as ethanol, followed by evaporation. Suitable acids for this reaction are, in particular, those which give physiologically acceptable acids. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, or sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example
® -15- formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethane- disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, naphthalenemono- and -disulfonic acids, and laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and/or purification of the compounds of the formula |.
The invention furthermore relates to the use of the compounds of the formula | as NHE-3 inhibitors and/or their physiologically acceptable salts for the preparation of pharmaceutical preparations, in particular by non- chemical methods. In this case, they can be converted into a suitable dosage form together with at least one solid, liquid and/or semiliquid excipient or assistant, and, if desired, in combination with one or more further active ingredients.
The invention furthermore relates to pharmaceutical preparations com- prising at least one NHE-3 inhibitor of the formula | and/or one of its physiologically acceptable salts and solvates.
These preparations can be used as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administra- tion and do no react with the novel compounds, for example water, vege- table oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, such as lactose or starch, magnesium stearates, talc or Vaseline. Suitable for oral administration are, in particu- lar, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal administration are suppositories, suitable for parenteral administration are solutions, preferably oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for topical application are ointments, creams or powders, or transdermally in patches.
PS -16 -
The novel compounds may also be lyophilised and the resultant lyophilisates used, for example, for the preparation of injection preparations. The preparations indicated may be sterilised and/or comprise assistants, such as lubricants, preservatives, stabilisers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, colorants and flavours and/or a plurality of further active ingredients, for example one or more vitamins.
Suitable pharmaceutical preparations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active ingredient of the formula | in a pharmaceutically acceptable solvent.
The compounds of the formula | and their physiologically acceptable salts and solvates can be used for the treatment and/or prophylaxis of the illnesses or iliness states described above.
In general, the substances according to the invention are preferably administered in doses between about 0.1 and 500 mg, in particular between 1 and 10 mg, per dosage unit. The daily dose is preferably between about 0.001 and 10 mg/kg of body weight. However, the specific dose for each patient depends on a wide variety of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and method of administration, on the excretion rate, medicament combination and severity of the particular illness to which the therapy applies. Oral administration is preferred.
Examples:
Example 1:
A mixture of 1.00 g of 2-amino-5-chloro-2‘-nitrobenzophenone, 0.60 g of 1-cyanoguanidine and 2.00 g of p-toluenesulfonic acid monohydrate was melted at 150°C for 2 hours. Methanol was added to the cooled melt, and the mixture was stirred at 65°C for 30 minutes. The residue obtained after filtration was discarded, and water was added to the filtrate. The solution
PN -17 - was subsequently rendered alkaline and extracted with ethyl acetate. The extract was evaporated and crystallised from acetonitrile, giving the free base N-[6-chioro-4-(2-nitrophenyl)quinazolin-2-yljguanidine. in order to form the acid-addition salt, the base was dissolved in methanol, the mixture was acidified using HCI-containing isopropanol, and the solvent was subsequently removed. Crystals of N-[6-chloro-4-(2-nitrophenyl)- quinazolin-2-yljguanidinium chloride were obtained from acetonitrile.
Example 2: 1.20 g of N-(5-methoxy-4-phenylquinazolin-2-yl)guanidinium chloride were stirred at 170°C for 6 hours with 8.00 g of pyridinium chloride. The cooled melt was subsequently treated with 20 ml of an Na»S204 solution. The resultant precipitate was isolated and dissolved in methanol, and the solution was acidified using HCl-containing isopropanol. After the solvent had been removed, the residue was crystallised from acetonitrile, giving N- (5-hydroxy-4-phenylquinazolin-2-yl)guanidinium chloride (m.p. 310°C).
Example 3:
A mixture of 3.01 g of 2-amino-5-chlorobenzophenone, 2.55 g of N-cyano-
N‘-methylguanidine and 7.42 g of p-toluenesulfonic acid monohydrate was stirred in the melt at from 150 to 160°C for 2 hours. Methanol was added to the cooled melt, and the mixture was stirred at 65°C for 30 minutes. The residue obtained after filtration was discarded, water and ethyl acetate were added to the filtrate, and the mixture was again stirred at 65°C for minutes. The product was subsequently allowed to crystallise out with stirring in an ice bath, giving N-(6-chloro-4-phenylquinazolin-2-yl)-N'- methylguanidinium p-toluenesulfonate (m.p. 268 — 269°C). 30 Example 4: 300 mg of N{6-chloro-4-(2-nitrophenyl)quinazolin-2-yljguanidinium p-toluenesulfonate were dissolved in 50 ml of methanol and hydrogenated at RT over the course of 21 hours at atmospheric pressure in the pressure of 300 mg of Raney nickel. Filtration and removal of the solvent gave N-[6- chloro-4-(2-aminophenyl)quinazolin-2-yljguanidinium p-toluenesulfonate from the filtrate. (m.p. 250°C).
® -18 -
Example 5:
A mixture of 0.350 g of N-(6-methylsulfanyl-4-phenylquinazolin-2-yl)- guanidinium chioride and 0.140 g of sodium perborate trinydrate in 5 mi of
S acetic acid was stirred at 80°C for 30 minutes. The solution was subse- quently evaporated and water was added. The aqueous solution was adjusted to pH 12 and extracted with ethyl acetate. Evaporation of the extract gave N-(6-methanesulfinyl-4-phenylquinazolin-2-yl)guanidine in crystalline form (m.p. 175 - 180°C).
Example 6:
A mixture of 1.200 g of N-(6-methylsulfanyi-4-phenylquinazolin-2-yi)- guanidinium chloride and 0.154 g of sodium perborate trihydrate in 5 ml of acetic acid was stirred at 80°C for 1 hour. The reaction mixture was subsequently evaporated, and water was added. The resultant solution was adjusted to pH 12 and extracted with ethyl acetate. Evaporation of the extract gave N-(6-methanesulfonyl-4-phenylquinazolin-2-yl)guanidine in crystalline form (m.p. 180 - 185°C).
In order to form the acid-addition salt, 0.80 g of N-(6-methanesulfonyl-4- phenylquinazolin-2-yl)guanidine were treated with an aqueous 1N HCI solution, and the resultant crystals were recrystallised from ethanol.
Example 7: 2.70 g of the hydrochloride of 2-amino-5-chlorobenzophenone and 1.70 g of N-cyano-N*,N“~dimethylguanidine were mixed and heated at 150°C for 3 hours. The reaction product was taken up in methanol and filtered. The filtrate was evaporated. The residue was recrystallised from a mixture of isopropanol and diethyl ether, giving N-(6-chloro-4-phenylquinazolin-2-yl)-
N',N"-dimethylguanidinium chloride (m.p. 264 - 267°C).
Example 8:
A mixture of 500 mg of 2-amino-5-chloro-2‘-nitrobenzophenone, 406 mg of
N-cyano-N‘-ethylguanidine and 1.03 g of p-toluenesulfonic acid mono- hydrate was stirred in the melt at from 150 to 160°C for 2 hours and worked up as in Example 3, giving N-[6-chloro-4-(2-nitrophenyl)quinazolin- 2-yl]-N'-ethylguanidinium p-toluenesuifonate (m.p. 298 - 300°C).
® oY
Example 9:
A mixture of 500 mg of 2-amino-5-chloro-2‘-nitrobenzophenone, 580 mg of
N-cyano-N-phenylguanidine and 1.03 g of p-toluenesulfonic acid monohydrate was stirred in the melt at from 150 to 160°C for 2 hours and worked up as in Example 3, giving N-[6-chloro-4-(2-nitrophenyl)quinazolin- 2-yl]-N'-phenylguanidinium p-toluenesulfonate (m.p. 261-263°C).
® -20-
The following acid-addition salts which are preferred as NHE-3 inhibitors were obtained analogously to the above-mentioned processes using the corresponding precursors: pTsOH denotes p-toluenesulfonic acid.
Examples 10 — 101:
R®
C
RY = HX
RZ oo
SN,
R'
R' R® R® R* HX (10) H Cl H SO.CH3 pTsOH (11) H cl CHs SO,CH; HCI (12) H Cl C2oHs SO.CHs HCI (13) H Cl OCHs SO.CH; HCI (14) H Cl NO: H pTsOH (15) H Cl NH, H pTsOH (m.p. 260-266°C) (16) H Cl N(CHs), H pTsOH (17) H Cl H NH- HCI (18) H Cl CHa NH: pTsOH (m.p. 211-214°C) (199 H Cl CoHs NH: HCI (20) H Cl OCH3 NH. HCI 21) H Cl NO, NH, HCI (22) H Cl NH: NH, HCI (23) H Cl N(CHs)2 NH: HCI (24) H Cl H NHCH; HCI (25) H Cl CHa NHCH; HCI (26) H Cl C:Hs NHCH; HCI (27) H Cl OCH3 NHCH; HCI
® -21- (28) H Cl NO, NHCH: HCI (29) H Cl NH.
NHCH; HCI (30) H Cl N(CHs)2 NHCHs HCI (31) H Cl H N(CHz), HCI (32) H Cl CHa N(CH3), HCI (33) H Cl CoHs N(CHs), HCI (34) H Cl OCH: N(CHs), HCI (35) H Cl NO» N(CHs). HCI (36) H Cl NH; N(CHs). HCI (37) H Cl N(CHs)2 N(CHs), HCI (38) H Cl H OH HCI (39) H Cl CH OH HC! (40) H Cl C2oHs OH HCI (41) H Cl OCH; OH HCI (42) H Cl NO.
OH HCI (43) H Cl NH; OH HCI (44) H Cl N(CHs), OH HCI (45) H Cl SO.CHs CHs HCI (46) H Cl H CN HCI (m.p. >350°, decomposition) (47) H Cl C2Hs SO,NH, HCI (48) H Cl OCF; CHs HCI (49) H Cl NO, CHs HCI (50) H Cl NH, CH3 HCI (51) H Cl N(CH3), CHs HCI (52) H Cl H NO, pTsOH (m.p. 313-315°C) (53) H Cl NO, H HCI (m.p. 346°C) (54) H H NH, H HCI (55) H H NH, CH3 HCI (56) H Cl CH CO-NH, HCI (57) H H CH; SO,CH3 pTsOH (58) H Cl OH F pTsOH (59) H Cl F SCH;3 HCI (60) H Br H CONH, pTsOH (61) H Br CO-NH, F pTsOH (62) H NO, H H pTsOH (m.p. 317-320°C)
® -22- (63) H OCH; H OCF3 pTsOH (64) H OH H H HC! (m.p. 333°C) (65) H NH, H H HCI (m.p. 290-296°C) (66) H SCHs H H HCI (m.p. 234-238°C) 67) H CH; CN CO-NH, pTsOH 68) H CeHs H H pTsOH (m.p. 188°C) (69) H CFs SOCHs H HCI (70) H OCF; H H HCI (m.p. 255-259°C) (71) H CN H H HCI (m.p. 330°C) (72) H F H SOC,Hs pTsOH (73) H SOCHs H H pTsOH (74) H SO,CH; H H pTsOH (75) H Cl CN H HCI (m.p. 344°C) (76) NH, CI Cl Cl HCI (77) H Cl H OCF3 pTsOH (m.p. 274-277°C) (78) H Cl OCF; H HCI (m.p. 310-315°C) (79) CI Cl CHs OH HCI (80) CI H NH, H HCI (81) CI H NH, CH; HCI (82) CHsz CI CHs COH HCI (83) CeHs CI CHs F HCI (84) OH CO-NH, H H pTsOH (85) Cl H H SCH; pTsOH (86) H Cl Cl SCH; pTsOH (87) SCH; H H H HCI (m.p. 303-306°C) (88) H F CHs CN HCI (89) H Cl SCH; H HCI (m.p. 324-327°C) (90) CH: H CN H HCI (91) H Cl CeHs H HCI (m.p. 200°C) (92) H Cl CHs NO> pTsOH (m.p. 210-214°C) (93) H H Br SO.CH; pTsOH (94) H H OCH; OCFs3 pTsOH (95) H Cl H CN HCI (m.p.>350°C, decomposition) (96) H Cl C2Hs NH, pTsOH (m.p.>257°C, decomposition)
® -23- 97) H cl CF NO, pTsOH (m.p. 304-308°C) (98) H Cl CHs NO, pTsOH (m.p. 286-287°C) (99) H cl SOCH; H HCI (mp. 322-324°C) (100) H Cl CFs NH, pTsOH (m.p.>232°C) (101) H Cl N(C.Hs), H HCI (m.p. 200°C)
Examples 102 — 154:
R>
RY ® R" uw hx
Sr
R’ SN,
R' R? R® R* HX (102) H cl H SO,CHs pTsOH (103) H Cl CHa SO,CHs HCI (404) H Cl CoHs SO.CHs HCI (105) H CI OCH; SO.CHs HCI (106) H Cl NO, H HCI (107) H Cl NH, H HCl (108) H Cl N(CHs}. H HCI (109) H cl H NH, HCI (110) H Cl CHs NH HCI (111) H Cl CuHs NH, HCI (112) H Cl OCH; NH; HCl (113) H Cl NO; NH, HCI (414) H Cl NH; NH, HCI (115) H Cl N(CHs)2 NH. HCI (116) H Cl H NHCHs HCI (117) H Cl CHs NHCHs HCI (118) H CI CoHs NHCHs HCI 3% (19) H Cl OCHs NHCHs HCI (120) H Cl NO, NHCHs HCI
® -24 - (121) H Cl NH: NHCH; HCI (122) H Cl N(CHs)2 NHCH; HCI (123) H Cl H N(CH), HCI (124) H Cl CH; N(CHs), HCI (125) H Cl C2Hs N(CH), HCI (126) H Cl OCH; N(CHs); HCI (127) H Cl NO, N(CH), HCI (128) H Cl NH; N(CHs), HCI (129) H Cl N(CHs)2 N(CHs), HCI (130) H Cl H OH HCI (131) H Cl CH; OH HCI (132) H Cl CoHs OH HCI (133) H Cl OCH: OH HCI (134) H Cl NO, OH HCI (135) H Cl NH» OH HCI (136) H Cl N(CHs), OH HCI (137) H Cl SCH; CHs HCI (138) H Cl CHs CHs HCI (139) H Cl C2Hs CHs HCI (140) H Cl OCH; CHs HCI (141) H Cl NO, CHa HCI (142) H Cl NH; CHs HCI (143) H Cl N(CHs), CHa HCI (144) H OCF3 NH, H HCI (145) H OCF; NH; CH HCI (146) H OCH3 SO,CH3 SO,CHs pTsOH (147) H OH H H pTsOH (148) CI OCH: NH: H HCI (149) CI Cl NH, CH; HCI (150) OCH; SCH; H H pTsOH (151) OH H H H HCI (m.p. 326°C) (152) Cli F H CONH, pTsOH (153) H CHs n-SCsH¢ H pTsOH (154) H Cl SO.NH, F pTsOH
® _25.-
Examples 155 — 205: rR>
Oe 2
R' SNE
R! R? R® R* HX (155) OH Cl H SO,CH; HCI (156) OH CI CH; SO, CHs HCI 1S 457) OH CC CHs SO, CHs HCI (158) OH CI OCH; SO,CH; HCI (159) OH Cl NO, H HCI (160) OH Cl NH, H HCI (161) OH CI N(CHs), H HCI 162) OH © H NH, HCI (163) OH CCH, NH, HCI (164) OH Cl CHs NH, HCI (165) OH CI OCH; NH, HCI (166) OH CI NO, NH, HCl 467) OH CNH» NH, HCl (168) OH CI N(CHs» NH, HC (169) OH CH NHCH; HCI (1700 OH Cl CHs NHCH; HCI (171) OH CI CHs NHCHs HCI 30° 4729 OH © OCH; NHCHs HCI (173) OH Cl NO» NHCHs; HCI (174) OH CI NH, NHCHs HCI (175) OH Cl N(CHs), NHCH; HCI (176) OH CH N(CHs), HCI 3 (477) OH Cl CHs N(CHs), HCI (178) OH Cl CsHs N(CH), HCI
PY - 26 - (179) OH Cl OCHs N(CHs), HCI (180) OH Cl NO. N(CH3); HCI (181) OH Cl NH. N(CHs), HCI (182) OH Cl N(CHs). N(CHs), HCI
S (183) OH Cl H OH OH (184) OH Cl CHs OH OH (185) OH Cl CoHs OH OH (186) OH Cl OCH; OH OH (187) OH Cl NO; OH OH (188) OH Cl NH; OH OH (189) OH Cl N(CHs), OH OH (190) OH Cl COCHs CHs HCI (191) OH Cl CHa CHs HCI (192) OH Cl CoHs CH; HC! (193) OH Cl OCH; CHs HCI (194) OH Cl NO; CHa HCI (195) OH Cl NH. CHs HCI (196) OH Cl N(CHs), CHs HCI (197) OH F NH. H HCI (198) OH F NH, CH3 HCI (199) OH F NH, H HCI (200) OH F NH. CH; HCI (201) OH OH H H HCI (m.p.290°C) (202) OCHs OCH; H CO.CH; pTsOH (203) Cl Cl COzH H HCI (204) CHs Cl CHs SCH HCI (205) Cl Cl SO.NH, H HCI
® 27 -
Examples 206 — 292:
R®
R*
C * HX
R2 ee P<
SNH,
R'
R' R? R® R* HX oo (2068) H Cl H NO. HC! (m.p. 342°C) (207) H Cl CHa NO, HCI (208) H Cl CzHs NO, HCI (209) H Cl OCH; NO: HCI (210) H of NO, NO HCI (211) H Cl NH. NO, HCI (212) H Cl N(CHs), NO: HCI (213) H Cl H NH, HCI (m.p. 300-340°C) (214) H of CHs NH, HCI (215) H Cl C2Hs NH, HCI (216) H of OCH; NH HCI (217) H Cl NO. NH HCI (218) H of NH. NH. HCI (219) H of N(CHs)> NH; HCI (220) H of H NHCH; HCI (221) H of CHs NHCH; HCI (222) H Cl C2Hs NHCH; HCI (223) H Cl OCH; NHCH; HCI (224) H Cl NO; NHCH; HCI (225) H Cl NH. NHCH; HCI (226) H Cl N(CHs)» NHCH; HCI (227) H Cl H N(CHs), HCI (228) H Cl CHs N(CHs). HCI
PY -28 - (229) H Cl C2Hs N(CHs). HCI (230) H Cl OCHs N(CHs)> HCI (231) H Cl NO; N(CHs), HCI (232) H Cl NH; N(CHs), HCI
S (233) H Cl N(CHs). N(CHs), HCI (234) H Cl H OH pTsOH (m.p. 252-254°C) (235) H Cl CH3 OH HCI (236) H Cl C2Hs OH HCI (237) H Cl OCH; OH HCI (238) H Cl NO, OH HCI (239) H Cl NH; OH HCI (240) H Cl N(CHs), OH HCI (241) H Cl CN CH; HCI (242) H Cl CHs CHs HCI (243) H of C2Hs CHs HCI (244) H Cl OCH; CHs; HCI (245) H Cl NO: CH; HCI (246) H Cl NH, CHa HCI (247) H ol N(CHs). CHa HCI (248) H Cl CONH, F HCI (249) H Cl NO: F HCI (250) H H NH, F HCI (251) H H NH; CH; HCI (252) H Cl SCH; Cl HCI (253) CeHs H CHa F HCI (254) CN Cl F F HCI (255) H Cl H CN HCI (m.p. 350°C) (256) H Br H CN HCI (257) H Br SOCH; F HCI (258) H NO, H F HCI (259) H OCH; CN F HCI (260) H OH H F HCI (261) H NH. H F HCI (262) H SCH H F HCH (263) H CH3 CONH, F HCI (264) H CeHs H F HCI
Ps -29 -
(265) H CF SOCH; F HCI
(266) H OCF; H F HCI
(267) H CN H F HCI
(268) H F SOCH; F HCI (269) H SOCH; H F HCI
(270) H SO,CHs H F HCI
(271) H Cl CN F HCI
(272) H Cl CONH, CI HCI
(273) H Cl H OCF; pTSOH (m.p. 260-264°C) (274) H Cl OCF: F HCI
(275) Cl Cl SO.NH, F HCI
(276) Cl H NH, F HCI
(277) Cli H NH, CHa HCI
(278) CH; Cl NHCH; F HCI (279) F Cl CH NHCH; HCI
(280) H H CeHs F HCI
(281) Cl NH.
F F HC!
(282) NH, Ci Cl F HCI
(283) SCHs H H F HCI (284) H F N(CHs), F HCI
(285) H Cl SCH; F HCI
(286) H H OCF; CHs HCI
(287) H Cl SOCH; H HCI (m.p. 240°C)
(288) H Cl CHs NH: pTsOH (m.p.217-218°C) (289) H Cl H OCF; HCI (m.p. 260-264°C)
(290) H Cl H CO.CH3 HCI (m.p. 275-277°C)
(291) H Cl CHa NO, pTsOH (m.p. 218-220°C)
(292) H Cl H NHCOCH; HCI (m.p. 317-320°C)
i ® -30 -
Examples 293 — 379:
R3 ® R* x HX
R2
CLE
SNE HGH, rR
R' R? R3 R* HX (293) H Cl H H pTsOH (m.p. 268-296°C) (294) H Cl CHs H HCI (m.p. 291-293°C) (295) H Cl CHs H HCI (296) H Cl OCH; H HCI (297) H Cl NO; H HCI (298) H Cl NH. H HCI (299) H Cl N(CHs), H HC! (300) H Cl H NH; HCI (301) H Cl CHs NH, HCI (302) H H H NH. pTsOH (m.p. 231-233°C) (303) H Cl OCH: NH» HCI (304) H Cl NO, NH. HCI (305) H Cl NH, NH; HCI (306) H Cl N(CHs). NH: HCI (307) H Cl H NHCHs; HCI (308) H Cl CHs NHCH; HCI (309) H Cl CzHs NHCH; HCI (310) H of OCH; NHCH; HC (311) H Cl NO. NHCH; HCI (312) H of NH, NHCH; HCI (313) H Cl N(CHs)» NHCHs HCI (314) H Cl H N(CHs), HCI (315) H Cl CHs N(CHs). HCI
PY -31- (316) H Cl CoHs N(CH), HCI (317) H Cl OCH; N(CHs), HCI (318) H Cl NO: N(CHz). HCI (319) H cl NH, N(CHs), HCI (320) H Cl N(CHs)2 N(CHs), HCI (321) H Cl H OH HCI (322) H Cl CHs OH HCI (323) H cl C2Hs OH HCI (324) H Cl OCH; OH HCI (325) H Cl NO, OH HCI (326) H Cl NH.
OH HCI (327) H Cl N(CHs), OH HCI (328) H Cl H CHs HCI (329) H Cl CHs CHs HCI (330) H Cl CoHs CHa HCI (331) H Cl OCH; CHa HCI (332) H Cl NO.
CH; HCI (333) H Cl NH, CHs HCI (334) H Cl N(CHs). CHa HCI (335) H Cl H NO» pTsOH (m.p. 278-279°C) (336) H Cl NO.
H HCI (337) H H NH.
H HCI (338) H H NH.
CH; HCI (339) H Cl CHs Cl HCI (340) H H CHs H HCI (341) H Cl H F HCI (342) H Cl F H HCI (343) H Br H H HCI (344) H Br H F HCI (345) H NO.
H H HCI (346) H OCHs H H HCI (347) H OH H H HCI (348) H NH, H H HCI (349) H SCH; H H HCI (350) H CH; H H HCI (351) H CeHs H H HCI
PY -32- (352) H CFs H H HCI (353) H OCF; H H HCI (354) H CN H H HCI (355) H F H H HCI (356) H SOCH; H H HCH (357) H SO,CH; H H HCI (358) H Cl CN H HCI (359) H Cl H Cl HCI (360) H Cl H OCF; HCI (361) H Cl OCF3 H HCI (362) CI Cl H H HCI (363) Cl H NH.
H HCI (364) CI H NH; CHa HCI (365) CH; CI CHs H HCI (366) F Cl CHs H HCI (367) H H H H pTsOH (m.p. 225-226°C) (368) CI H H H HCI (369) H Cl Cl H HCI (370) SCHs H H H HCI (371) H F CHs H HCI (372) H Cl SCH» H HCI (373) CH; H H H HCI (374) H Cl CesHs H HCI (375) H Cl CHs NO: HCI (376) H H Br H HCI (377) H H OCH; H HCI (378) H H H NH; HCI (379) H Cl H NH. pTsOH (m.p. 252-254°C)
® -33-
Examples 380 — 465:
R3
C R* * HX 2
SENG),
R'
R' R? R® R* HX (380) H Cl H H pTsOH (m.p. 216-217°C) (381) H Cl CHa H pTSOH (m.p. 176-177°C) (382) H Cl CoHs H HCI (383) H of OCHs H HCI (384) H Cl NO H HCI (385) H Cl NH; H HCI (386) H Cl N(CH3), H HCI (387) H Cl H NH; HCI (388) H Cl CHa NH; HCI (389) H H H NH pTsOH (m.p. >200°C, decomposition) (390) H Cl OCH; NH; HCl (391) H Cl NO, NH-> HCI (392) H Cl NH; NH: HCI (393) H Cl N(CHs), NH: HC! (394) H Cl H NHCHs HCI (395) H of CHs NHCHs; HCI (396) H Cl CzHs NHCH; HCI (397) H Cl OCH; NHCH; HCI (398) H Cl NO NHCH; HCI (399) H Cl NH, NHCH; HCI (400) H Cl N(CHs), NHCH; HCI (401) H Cl H N(CHs)2 HCI
PY -34- (402) H Cl CHa N(CHs), HCI (403) H Cl C2Hs N(CHs), HCI (404) H Cl OCHs N(CHs); HCI (405) H Cl NO> N(CHs); HCI (406) H Cl NH; N(CHs), HCI (407) H Cl N(CHs)2 N(CH), HCI (408) H Cl H OH HC! (409) H Cl CHa OH HCI (410) H Cl C.Hs OH HCI (411) H Cl OCH; OH HCI (412) H Cl NO, OH HCI (413) H Cl NH, OH HC! (414) H Cl N(CHs), OH HCI (415) H Cl H CHa HCI (416) H Cl CHa CH HCI (417) H Cl CoHs CHs HCI (418) H Cl OCH; CH; HCI (419) H Cl NO, CH HCI (420) H Cl NH.
CHa HCI (421) H Cl N(CH3), CHa HCI (422) H Cl H NO, pTsOH (m.p. 233-235°C) (423) H Cl NO, H HCI (424) H H NH, H HCI (425) H H NH.
CH; HCI (426) H Cl CHs Cl HCI (427) H H CH; H HCI (428) H Cl H F HCI (429) H Cl F H HCI (430) H Br H H HCI (431) H Br H F HCI (432) H NO, H H HCI (433) H OCH3 H H HCI (434) H OH H H HCI (435) H NH, H H HC! (436) H SCH; H H HCI (437) H CH; H H HCI
PS -35- (438) H CeHs H H HCI (439) H CFs; H H HCI (440) H OCF; H H HCI (441) H CN H H HCI (442) H F H H HCI (443) H SOCHs H H HCI (444) H SO,CH; H H HCI (445) H Cl CN H HC! (446) H Cl H Cl HCI (447) H Cl H OCF; HCI (448) H Cl OCF; H HCI (449) Cl of H H HCI (450) Cl H NH; H HCI (451) CI H NH.
CHs HCI (452) CHs CI CH3 H HCI (453) F of CHs H HCI (454) H H H H HCI (455) Cl H H H HCI (456) H Cl Cl H HCI (457) SCH; H H H HC! (458) H F CHs H HCI (459) H Cl SCH; H HCI (460) CH: H H H HCI (461) H Cl CeHs H HCI (462) H Cl CH NO: HCI (463) H H Br H HCI (464) H H OCHs H HCI (465) H H H NH.
HCI
® -36 -
Examples 466 — 552:
R> ®
R* * HX 2
SNE
R'
R' R? R® R* HX (466) H Cl H H pTsOH (m.p. 236-238°C) (467) H Cl CHa H pTsOH (m.p. 244-246°C) (468) H Cl CoHs H HCI (469) H Cl OCHs H HCI (470) H Cl NO. H HCI (471) H Cl NH, H HCI (472) H Cl N(CHs), H HC] (473) H Cl H NH. HCI (474) H of CHa NH. HCI (475) H H H NH; pTsOH (m.p. >200°C, decomposition) (476) H Cl OCHs NH: HCI (477) H (of NO. NH; HCI (478) H Cl NH, NH; HC! (479) H Cl N(CH) NH: HCI (480) H Cl H NHCHs HCI (481) H Cl CHs NHCH; HCI (482) H (of C2Hs NHCH; HCI (483) H Cl OCH; NHCHs; HCI (484) H Cl NO. NHCH; HCI (485) H Cl NH; NHCHs HCI (486) H Cl N(CH3)2 NHCHs HCI (487) H of H N(CHs). HCI (488) H Cl CHa N(CHs), HCI
PY -37- (489) H Cl C2Hs N(CH), HCI (490) H Cl OCHs N(CHs)2 HCI (491) H Cl NO, N(CHz), HCI (492) H Cl NH; N(CHs). HCI (493) H Cl N(CHs)2 N(CH), HCI (494) H Cl H OH HCI (495) H Cl CHa OH HCI (496) H Cl CoHs OH HCI (497) H Cl OCH; OH HCI (498) H Cl NO: OH HCI (499) H Cl NH; OH HCI (500) H Cl N(CHs) OH HCI (501) H Cl H CH3 HCI (502) H Cl CHs CHs3 HCI (503) H Cl C2Hs CH; HCI (504) H Cl OCH; CHs HCI (505) H Cl NO CHs HCI (506) H Cl NH.
CHs HCI (507) H Cl N(CHs). CHs HCI (508) H Cl H NO.
HCI (509) H Cl NO H HCI (510) H H NH, H HCI (511) H H NH.
CHs HCI (512) H Cl CH; Cl HCI (513) H H CHs H HCI (514) H Cl H F HCI (515) H Cl F H HCI (516) H Br H H HCI (517) H Br H F HCI (518) H NO, H H HCI (519) H OCH; H H HCI (520) H OH H H HCI (521) H NH, H H HCI (522) H SCH3 H H HCI (523) H CH H H HCI (524) H CeHs H H HCI
PS -38- (525) H CFs H H HCI (526) H OCFs H H HCI (527) H CN H H HCI (528) H F H H HCI (529) H SOCH; H H HCI (530) H SO,CH; H H HCI (531) H Cl CN H HCI (532) H Cl H Cl HCI (533) H Cl H OCF; HCI (534) H Cl OCF; H HCI (535) Cli Cl H H HCI (536) CI H NH.
H HCI (537) CI H NH.
CHs HCI (538) CH; CI CHs H HCI (539) F Cl CHs H HCI (540) H H H H HCI (541) CI H H H HCI (542) H Cl Cl H HCI (543) SCH; H H H HCI (544) H F CH; H HCI (545) H Cl SCH; H HCI (546) CHs H H H HCI (547) H Cl CeHs H HCI (548) H Cl CH NO- HCI (549) H H Br H HCI (550) H H OCH; H HC! (551) H H H NH, HCI (552) H Cl H NH, pTsOH (m.p. 231-232°C)
PS -39-
Examples 553— 639:
R®
Ow
RZ
9K N NHCH,
SNH,
R'
R' R? R® R* HX (553) H Cl H H pTsOH (554) H Cl CH; H HCI (555) H Cl CoHs H HCI (556) H Cl OCH: H HCI (657) H of NO H HCI (558) H of NH. H HCI (559) H Cl N(CHs); H HCI (560) H of H NH; HCI (m.p. 298-301°C) (561) H Cl CH; NH; HCI (562) H Cl CzHs NH; HCI (563) H Cl OCH; NH; HCI (564) H Cl NO. NH, HCI (565) H (of NH; NH; HCI (566) H Cl N(CHs), NH: HCI (567) H Cl H NHCH; HCI (568) H of CH; NHCHs HCI (569) H of CzHs NHCHs HCI (570) H Cl OCH: NHCHs HCI (571) H Cl NO; NHCH; HCI (572) H Cl NH. NHCH; HCI (573) H Cl N(CHs), NHCHs HCI (574) H Cl H N(CHs), HCI (575) H of CHs N(CHs), HCI
PY - 40 - (576) H Cl C2Hs N(CHs), HCI (577) H Cl OCHs N(CHs), HCI (578) H Cl NO N(CHs), HCI (579) H Cl NH: N(CH), HCI
S (580) H Cl N(CH3)2 N(CHj), HCI (581) H Cl H OH HCI (582) H Cl CHa OH HCI (583) H Cl CoHs OH HCI (584) H Cl OCHs OH HCI (585) H Cl NO OH HCI (586) H Cl NH. OH HCI (587) H Cl N(CH3). OH HCI (588) H Cl H CHa HCI (589) H Cl CH; CH; HCI (590) H Cl CoHs CH3 HCI (591) H Cl OCH; CHa HCI (592) H Cl NO; CHa HCI (593) H Cl NH. CHs HCI (594) H Cl N(CHz). CHs HCI (595) H Cl H NO. pTsOH (m.p. 217-220°C) (596) H Cl NO, H HCI (597) H H NH; H HCI (598) H H NH, CHs HCI (599) H Cl CHa Cl HCI (600) H H CHs H HCI (601) H Cl H F HCI (602) H Cl F H HCI (603) H Br H H HCI (604) H Br H F HCI (605) H NO H H HCI (606) H OCH; H H HCI (607) H OH H H HCI (608) H NH, H H HCI (609) H SCH H H HCI (610) H CHs H H HCI (611) H CeHs H H HCI
PS -41 - (612) H CFs H H HCI (613) H OCF; H H HCI (614) H CN H H HCI (615) H F H H HCI (616) H SOCHs H H HCI (617) H SO,CH; H H HC! (618) H Cl CN H HCI (619) H Cl H Cl HCI (620) H Cl H OCF; HCI (621) H Cl OCF; H HCI (622) Cli Cl H H HCI (623) Cl H NH H HCI (624) CI H NH CHs HCI (625) CH; Cl CHs H HCI (626) F Cl CHs H HCI (627) H H H H HCI (628) CI H H H HCI (629) H Cl Cl H HCI (630) SCH; H H H HCI (631) H F CHs H HCI (632) H Cl SCH; H HCI (633) CHs H H H HCI (634) H Cl CeHs H HCI (635) H Cl CHs NO.
HCI (636) H H Br H HCI (637) H H OCH; H HCI (638) H Cl H NH. pTsOH (639) H Cl H NO: HCI
PS 42 -
Examples 640 — 726:
R>
Je
RZ ee Ve
SNNENHO A,
R' rR rR rR rR wx (640) H Cl H H HCI (641) H Cl CHs H HCI (642) H Cl CoHs H HCI (643) H Cl OCH; H HC! (644) H Cl NO H HC (645) H Cl NH. H HCI (646) H Cl N(CHs), H HCI (647) H Cl H NH. pTsOH (m.p. 178-180°C) (648) H Cl CHs NH: HCI (649) H Cl CoHs NH; HCI (650) H of OCHs NH; HCI (651) H Cl NO, NH; HCI (652) H of NH. NH; HCI (653) H of N(CHs). NH: HC! (654) H Cl H NHCHs; HCI (655) H of CHs NHCHs HCI (656) H Cl CoHs NHCH; HCI (657) H Cl OCHs NHCH; HCI (658) H of NO; NHCHs HCI (659) H Cl NH. NHCHs HCI (660) H Cl N(CHs), NHCHs; HCI (661) H Cl H N(CHz), HCI (662) H of CHa N(CH3), HCI
PS - 43 - (663) H of C2Hs N(CH), HCI (664) H Cl OCHs N(CHs), HCI (665) H Cl NO. N(CH); HCI (666) H Cl NH; N(CH3), HCI
S (667) H Cl N(CHs)2 N(CHs), HCI (668) H Cl H OH HCI (669) H Cl CHs OH HCI (670) H Cl CoHs OH HCI (671) H Cl OCH: OH HCI (672) H Cl NO, OH HCI (673) H Cl NH. OH HCI (674) H Cl N(CHs), OH HCI (675) H Cl H CHa HCI (676) H Cl CH; CHa HCI (677) H Cl CoHs CH; HCI (678) H Cl OCH: CHgs HCI (679) H Cl NO CH; HCI (680) H Cl NH. CHa HCI (681) H Cl N(CHs), CHs HCI (682) H Cl H NO, HCI (683) H Cl NO; H HCI (684) H H NH. H HC! (685) H H NH, CH; HCI (686) H Cl CH; Cl HCI (687) H H CHs H HCI (688) H Cl H F HCI (689) H Cl F H HCI (690) H Br H H HCI (691) H Br H F HCI (692) H NO, H H HCI (693) H OCHs H H HCI (694) H OH H H HCI (695) H NH, H H HCI (696) H SCH; H H HCI (697) H CH; H H HCI (698) H CeHs H H HCI
PS -44 - (699) H CFs H H HCI (700) H OCF; H H HCI (701) H CN H H HCI (702) H F H H HCI (703) H SOCH; H H HC! (704) H SO,CHs H H HCI (705) H Cl CN H HCI (706) H Cl H Cl HCI (707) H Cl H OCF; HCI (708) H Cl OCF; H HCI (709) Cl Cl H H HCI (710) Cli H NH; H HCI (711) CI H NH, CHs HCI (712) CH; CI CHa H HCI (713) F Cl CHs H HCI (714) H H H H HCI (715) Cl H H H HCI (716) H Cl (of H HCI (717) SCH; H H H HCI (718) H F CHa H HCI (719) H Cl SCH; H HCI (720) CHs H H H HCI (721) H Cl CeHs H HCI (722) H Cl CHs NO> HCI (723) H H Br H HCI (724) H H OCH; H HC! (725) H Cl H NH, pTsOH (m.p. 178-180°C) (726) H Cl H H pTsOH (m.p. 219-220°C)
® - 45.
Examples 727 — 813:
R®
Ow 2
SSN
R' )
RR rR rR rR wx (727) H Cl H H HCI (m.p. 250-252°C) 5 (728) H Cl CHa H HCI (729) H Cl CHs H HCI (730) H Cl OCH; H HCI (731) H cl NO. H HCI (732) H Cl NH H HCI (733) H cl N(CH). H HCI (734) H Cl H NH, pTsOH (735) H Cl CH; NH. HCI (736) H Cl CoHs NH. HCI (737) H Cl OCH; NH. HCI (738) H Cl NO. NH. HCI (739) H Cl NH. NH. HCI (740) H Cl N(CHz): NH. HCI (741) H Cl H NHCHs; HCI (742) H Cl CHa NHCHs; HCI (743) H Cl CoHs NHCHs; HCI (744) H Cl OCH; NHCHs; HCI (745) H Cl NO, NHCH; HCl (746) H ci NH. NHCHs HCI (747) H Cl N(CHs) NHCHs; HCI (748) H cl H N(CHs). HCI (749) H Cl CHs N(CH), HCI

Claims (1)

  1. } ® Patent Claims
    1. Compounds of the formula Ar R2 ~ °N Sy Rt in which
    5.6 6 NR'R NR Y IS or R® Ar is phenyl or naphthyl, each of which is unsubstituted or monosubstituted by R® and/or R?, R! RZ R® and R* are each, independently of one another, H, A, OA, Hal, CF3, OH, NO2, NH,, NHA, NA, NH-CO-A, NH-CO-Ph, SA, SO-A, SO--A, SO-Ph, CN, OCF3, CO-A, COzH, COA, CO-NH,, CO-NHA, CO-NA;, SO2NH;, SO;NHA, SONA, or phenyl which is unsubstituted or monosubstituted or poly- substituted by A, OA, Hal or CF3, A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, Hal isF, Cl Brorl R° R® R” and R® are each, independently of one another, H, A, or phenyl which is unsubstituted or monosubstituted or polysubstituted by A, OA, Hal or CF3, where R® and R’, R® and R®, and R’ and R® are able to form 5-7-membered rings,
    CY -59 - and their salts and solvates, with the proviso that compounds in which RS R® R’ and R® are simultaneously H and none of the radicals R’, RZ Rand R*is OH, NO3, NH;, NHA, NA;, NH-CO-A, NH-CO-Ph,
    SA. SO-A, SOA, SO2-Ph, CN, OCF3, CO-A, CO2H, CO2A, CO-NH, CO-NHA, CO-NA;, SO,NH,, SO,NHA, SO2NA;, or phenyl which is unsubstituted or monosubstituted or polysubstituted by A, OA, Hal or CFs, are excluded.
    2. Compounds of the formula | according to Claim 1 and their salts and solvates as NHE-3 inhibitors.
    3. Compounds of the formula | according to Claim 1 and their physio- logically acceptable salts or solvates for use in combating illnesses.
    4. Use of compounds of the formula 1 according to Claim 1 and/or their physiologically acceptable salts or solvates for the preparation of a medicament.
    5. Use of compounds of the formula | according to Claim 1 and their physiologically acceptable salts and/or solvates for the preparation of a medicament for the treatment of hypertonia, thrombosis, ischaemic states of the heart, of the peripheral and central nervous system and of strokes, ischaemic states of peripheral organs and limbs, and for the treatment of shock states.
    6. Use of compounds of the formula | according to Claim 1 and their physiologically acceptable salts and/or solvates for the preparation of a medicament for use in surgical operations and organ transplants and for the preservation and storage of transplants for surgical measures.
    7. Use of compounds of the formula | according to claim 1 and their physiologically acceptable salts and/or solvates for the preparation of a medicament for the treatment of illnesses in which cell proliferation represents a primary or secondary cause, for the treatment or
    ® -60 - prophylaxis of disorders of fat metabolism or disturbed breathing drive.
    8. Use of compounds of the formula | according to Claim 1 and their S physiologically acceptable salts and/or solvates for the preparation of a medicament for the treatment of renal ischaemia, ischaemic intestinal illnesses or for the prophylaxis of acute or chronic renal illnesses.
    9. Use of compounds of the formula | according to Claim 1 and their physiologically acceptable salts and/or solvates for the preparation of a medicament for the treatment of bacterial and parasitic illnesses.
    10. Pharmaceutical preparation, characterised by a content of at least one NHE-3 inhibitor according to Claim 1 and/or one of its physio- logically acceptable salts and/or solvates.
    11. Compound selected from the group consisting of the compounds I1 to 110: N-(6-chloro-4-phenylquinazolin-2-yl)-N'-methylguanidine 11 N-(6-chloro-4-p-tolylquinazolin-2-yl)-N'-methylguanidine 12 N-[6-chloro-4-(2-nitrophenyl)quinazolin-2-y{]-N'-methyl- 13 guanidine N-[4-(2-aminophenyl)-6-chloroquinazolin-2-yl]-N'-methy!- 14 guanidine N-[6-chloro-4-(4-methyl-2-nitrophenyl)quinazolin-2-yl]-N'- 15 methylguanidine N-[4-(2-amino-4-methylphenyl)-6-chloroquinazolin-2-yl]-N'- 16 methylguanidine N-[6-chloro-4-(2-nitrophenyl)quinazolin-2-yljguanidine 17 N-[4-(2-aminophenyl)-6-chloroquinazolin-2-yljguanidine 18 N-[6-chloro-4-(4-methyl-2-nitrophenyl)quinazolin-2-yl]- 19 guanidine N-{4-(2-amino-4-methylphenyl)-6-chloroquinazolin-2-yi]- 110 guanidine
    ® or and their salts and solvates.
    12. Compounds according to Claim 1 as medicament active ingredients.
    13. Process for the preparation of the 2-guanidino-4-arylquinazolines of the formula | and their salts and solvates, characterised in that either (a) compounds of the formula ll Ar R? 0] NH, R? in which R'. R? and Ar are as defined above, are reacted with 1-cyanoguanidine or a correspondingly N-alkylated or N-arylated cyanoguanidine of the formula NC-Y, in which Y is as defined in Claim 1, or (b) instead of a compound of the formula NC-Y, a compound of the formula lil HN=CX-Y Ib in which X is -S-alkyl, -S-aryl, -O-alkyl or -O-aryl, is reacted with a compound of the formula II, or (c) 2-chloro-4-arylquinazolines of the formula IV
    ® oe Ar R2 ZN \ \Y; NS oc
    R?
    in which Ar, R' and R? are as defined in Claim 1,
    are reacted with a compound of the formula HY, in which Y is as defined in Claim 1,
    and optionally, after steps (a), (b) or (c), a basic or acidic compound of the formula | is converted into one of its salts or solvates by treat-
    ment with an acid or base.
ZA200302633A 2000-09-05 2003-04-03 2-Guianidino-4-arylquinazolines. ZA200302633B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE10043667A DE10043667A1 (en) 2000-09-05 2000-09-05 2-guanidino-4-aryl-quinazolines

Publications (1)

Publication Number Publication Date
ZA200302633B true ZA200302633B (en) 2004-09-08

Family

ID=7655015

Family Applications (1)

Application Number Title Priority Date Filing Date
ZA200302633A ZA200302633B (en) 2000-09-05 2003-04-03 2-Guianidino-4-arylquinazolines.

Country Status (16)

Country Link
US (1) US20040039001A1 (en)
EP (1) EP1315704A1 (en)
JP (1) JP2004508360A (en)
KR (1) KR20030062404A (en)
CN (1) CN1450996A (en)
AU (1) AU2001285886A1 (en)
BR (1) BR0113583A (en)
CA (1) CA2421222A1 (en)
CZ (1) CZ2003858A3 (en)
DE (1) DE10043667A1 (en)
MX (1) MXPA03001877A (en)
NO (1) NO20030999D0 (en)
PL (1) PL360391A1 (en)
RU (1) RU2003108861A (en)
WO (1) WO2002020496A1 (en)
ZA (1) ZA200302633B (en)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10163992A1 (en) * 2001-12-24 2003-07-03 Merck Patent Gmbh 4-aryl-quinazolines
US20050054705A1 (en) 2003-02-04 2005-03-10 Aventis Pharma Deutschland Gmbh N-substituted (benzoimidazol-2-yl) phenylamines, process for their preparation, their use as medicament or diagnostic aid, and medicament comprising them
DE10304374A1 (en) 2003-02-04 2004-08-05 Aventis Pharma Deutschland Gmbh Novel substituted 2-aminoimidazoles, process for their preparation, their use as medicament or diagnostic agent and medicament containing them
WO2009046448A1 (en) * 2007-10-04 2009-04-09 Intellikine, Inc. Chemical entities and therapeutic uses thereof
WO2018129556A1 (en) 2017-01-09 2018-07-12 Ardelyx, Inc. Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
EP2384318B1 (en) 2008-12-31 2017-11-15 Ardelyx, Inc. Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
US20120088737A2 (en) * 2009-10-02 2012-04-12 Ajinomoto Co., Inc Novel acyl guanidine derivatives
KR102038462B1 (en) 2011-12-15 2019-10-31 노파르티스 아게 Use of inhibitors of the activity or function of PI3K
US20150336892A1 (en) 2012-08-21 2015-11-26 Ardelyx, Inc Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
US10376481B2 (en) 2012-08-21 2019-08-13 Ardelyx, Inc. Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders
KR102287207B1 (en) 2013-04-12 2021-08-09 알데릭스, 인코포레이티드 Nhe3-binding compounds and methods for inhibiting phosphate transport
EA201991676A1 (en) 2017-01-09 2020-01-30 Арделикс, Инк. NHE-MEDIATED ANTI-PORT INHIBITORS
MX2019008170A (en) 2017-01-09 2020-02-07 Ardelyx Inc Compounds useful for treating gastrointestinal tract disorders.
EA202090438A1 (en) 2017-08-04 2020-06-15 Арделикс, Инк. Glycerretic Acid Derivatives for the Treatment of Hyperkalemia
AU2020218255A1 (en) 2019-02-07 2021-09-09 Ardelyx, Inc. Glycyrrhetinic acid derivatives for use in treating hyperkalemia
WO2020237096A1 (en) 2019-05-21 2020-11-26 Ardelyx, Inc. Combination for lowering serum phosphate in a patient

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3131187A (en) * 1964-04-28 Certain z-guantoino-x-aryl-quinazolines
JPH11209350A (en) * 1998-01-26 1999-08-03 Eisai Co Ltd Nitrogen-containing heterocyclic derivative and medicine containing the same
DE10019062A1 (en) * 2000-04-18 2001-10-25 Merck Patent Gmbh Use of known and new 2-guanidino-4-aryl-quinazoline derivatives as NHE-3 inhibitors useful for the treatment of e.g. hypertension, thrombosis, cardiac ischemia, peripheral and CNS ischemia
US20030139431A1 (en) * 2001-09-24 2003-07-24 Kawakami Joel K. Guanidines which are agonist/antagonist ligands for neuropeptide FF (NPFF) receptors
DE10163992A1 (en) * 2001-12-24 2003-07-03 Merck Patent Gmbh 4-aryl-quinazolines

Also Published As

Publication number Publication date
CZ2003858A3 (en) 2003-06-18
DE10043667A1 (en) 2002-03-14
AU2001285886A1 (en) 2002-03-22
CN1450996A (en) 2003-10-22
NO20030999D0 (en) 2003-03-04
KR20030062404A (en) 2003-07-25
US20040039001A1 (en) 2004-02-26
BR0113583A (en) 2003-07-15
MXPA03001877A (en) 2003-06-24
RU2003108861A (en) 2004-09-20
EP1315704A1 (en) 2003-06-04
WO2002020496A1 (en) 2002-03-14
PL360391A1 (en) 2004-09-06
JP2004508360A (en) 2004-03-18
CA2421222A1 (en) 2003-03-03

Similar Documents

Publication Publication Date Title
ZA200302633B (en) 2-Guianidino-4-arylquinazolines.
ZA200209274B (en) 2-Guanidino-4-arylquinazolines as NHE-3 inhibitors.
US20050020612A1 (en) 4-Aryliquinazolines and the use thereof as nhe-3 inhibitors
EP0810217A1 (en) Pyrazole derivatives and their pharmaceutical use as smooth muscle cell growth inhibitors
SK6822003A3 (en) Substituted 2-anilino-benzimidazoles and the use thereof as NHE-inhibitors
JP3875731B2 (en) 3,5-substituted aminobenzoylguanidines, their preparation, their use as medicaments or diagnostics and medicaments containing them
US20050113396A1 (en) 2-Guanidino-4-heterocyclylquinazolines
KR20010013026A (en) Cyanoguanidines as cell proliferation inhibitors
PL180902B1 (en) Novel derivatives of alkyl-benzoyl guanidine, method of obtaining them and pharmaceutic preparation and method of preparing same
JP5249918B2 (en) Substituted 1-amino-4-phenyl-dihydroisoquinolines, processes for their preparation, their use as drugs, and drugs containing them
EP1664058B1 (en) Substituted thienoimidazoles, method for production and use thereof as medicament or diagnostic and medicaments comprising the same
PL208284B1 (en) Benzo [g] quinoline derivatives for treating glaucoma and myopia
CZ274495A3 (en) Derivative of alkyl-5-methylsulfonyl benzoguanidine, process of its preparation and pharmaceutical composition containing thereof
PL182184B1 (en) Novel derivatives of heterocycloxy-benzoguanidine, method of obtaining such derivatives as well as pharmaceutical agent and method of obtaining same
EP1999112A2 (en) Substituted 2-amino-4-phenyl-d hydroquinolines, method for the production thereof, use thereof as medicaments, and medicaments containing them
US6117867A (en) Substituted 6-R-1,3,4-thiadiazine-2-amines, the use thereof as anaesthetizing, cardiovascular and hypometabolic agents, and a pharmaceutical composition containing them
US6313111B1 (en) Substituted 6H-1,3,4-thiadiazine-2-amines, the use thereof as anaesthetising, cardiovascular and hypometabolic agents, and pharmaceutical composition containing them
CS203060B2 (en) Process for preparing new derivatives of n-/3,3-diphenylpropyl/propylendiamine